Mass spectra data were obtained for selected compounds of Tables I to XXIX on Micromass Platform 2 machines. The data are shown in Table 3.
(Table Removed)
Mass spectra data were obtained for selected compounds of Tables XXX to XXXII using LC1-4S: LC5: 254nm - gradient 10% A to 100% B A=H2O+0.01%HCOOH B=CH3CN/CH3OH+0.01%HCOOH positive electrospray 150-1000 m/z
The data are shown in Table 4.
Table 4
(Table Removed)
The compounds'of the invention may be made in a variety of ways. For example they may be made by the reactions summarised in Scheme I.
(Scheme Removed)
Thus a compound of formula 1 may be synthesised from compounds of formula 2a or 2b by reaction with an alkylating agent of the formula R8-L, where L is chloride, bromide, iodide or a sulfonate (e.g. mesylate or tosylate) or similar leaving group at a temperature of between ambient temperature and 100°C, typically 65°C, in an organic solvent such as dichloromethane, chloroform or 1,2-dichloroethane in the presence of a tertiary amine base such as triethylamine or diisopropylethylamine and optionally catalysed by halide salts such as sodium iodide, potassium iodide or tetrabutylammonium iodide.
Alternatively, a compound of formula 2a or 2b may be reacted with an aldehyde of the formula RCHO at a temperature between ambient temperature and 100°C in an organic solvent such as tetrahydrofuran or ethanol or mixtures of solvents in the presence of a reducing agent such as borane-pyridine complex, sodium borohydride, sodium (triacetoxy)borohydride, sodium cyanoborohydride or such like, to produce a compound of formula 1 where R8 is CH2-R.
Alternatively, a compound of formula 2a or 2b may be reacted with paraformaldehyde and a boronic acid of the formula R-B(OH)2 at a temperature between ambient temperature and 100°C in an organic solvent such as ethanol, 1,4-dioxane or water to produce a compound of formula 1 where R8 is CH2-R.
A compound of formula 2a may be obtained from a compound of formula 3 by reaction with an acid such as trifluoroacetic acid at ambient temperature in an organic solvent such as dichloromethane, chloroform or 1,2-dichloroethane followed by neutralisation of the reaction mixture with an aqueous solution of an inorganic base such as sodium carbonate, sodium bicarbonate or similar compound.
Similarly a compound of formula 2b may be formed by reaction of a compound of formula 3 with an acid such as trifluoroacetic acid at ambient temperature in an organic solvent such as dichloromethane, chloroform or 1,2-dichloroethane followed by evaporation of the solvents and trituration with organic solvents such as ether or hexane.
Compounds of formula 3 may be obtained from compounds of formula 4 by reaction with a suitable electrophilic species. Compounds of formula 3 where Y is a carbonyl group may be formed by the reaction of compounds of formula 4 with a carboxylic acid derivative of formula R1-C(O)-Z where Z is chloride, hydroxy, alkoxy or acyloxy at a temperature between 0°C and 150°C optionally in an organic solvent such as dichloromethane,
chloroform or 1,2-dichloroethane, optionally in the presence of a tertiary amine base such as triethylamine or diisopropylethylamine and optionally in the presence of a coupling agent such as dicyclohexylcarbodiimide. Compounds of formula 3 where Y is a carbonyl group-and Rl is an amino substituent of formula R'-NH- may be formed by the reaction of compounds of formula 4 with an isocyanate of formula R'-N=C=O under similar conditions. Compounds of formula 3 where Y is a group of formula S(O)q may be formed from compounds of formula 4 by treatment with compounds of formula of Rl-S(O)q-Cl under similar conditions. Compounds of formula 3 where Y is a thiocarbonyl group and Rl is an amino substituent of formula R'-NH- may be formed by the reaction of compounds of formula 3 with an isothiocyanate of formula R'-N=C=S under similar conditions. Alternatively compounds of formula 3 where Y is a thiocarbonyl group and Rl is a carbon substituent may be formed by treatment of compounds of formula 3 where Y is a carbonyl group and Rl is a carbon substituent with a suitable thionating agent such as Lawesson's reagent.
In the above procedures, acid derivatives of the formula R1-C(O)-Z, isocyanates of formula R'-N=C=O, isothiocyanates of formula R'-N=C=S and sulfur electrophiles of formula Rl-S(O)q-Cl are either known compounds or may be formed from known compounds by known methods by a person skilled in the art.
Compounds of formula 4 may be obtained by reacting compounds of formula 5 with compounds of formula 6 at a temperature of between 0°C and 100°C in an organic solvent such as dichloromethane, chloroform or 1,2-dichloroethane in the presence of an acid such as hydrochloric acid or trifluoroacetic acid and a co-solvent such as water, methanol or ethanol, or in the presence of a Lewis acidic metal salt such as a zinc(II) dihalide. The intermediates formed (compounds of formula 4a) are subsequently treated with a nucleophile R3-M (where M is a metallic species. R3-M is for example a Grignard reagent) or, when R3 is hydrogen, a reducing agent such as sodium borohydride, sodium (triacetoxy)borohydride, sodium cyanoborohydride or similar at ambient temperature in organic solvent such as ethanol or chloroform. The basic procedure is described in Tetrahedron (1997), 53, 10983-10992.
Compounds of formula 6 may be obtained from compounds of formula 7 by reaction with a 1-alkoxy substituted phosphonium salt such as
methoxymethyl(triphenyl)phosphonium chloride and a base such as potassium tert-butoxide at a temperature of 0°C to room temperature in tetrahydrofuran.
Compounds of formula 5 and 7 are either known compounds or may be obtained from known compounds by known techniques.
Certain compounds of formula 2, 3, 4,4a and 6 are novel and as such form a further aspect of the invention.
Further procedures for making compounds of formula 1' (compounds of formula I where R2, R3, R9 and R10 are all hydrogen) are illustrated in scheme II below

(Scheme Removed)
Thus a compound of formula 1' may be obtained from a compound of formula 8 by reaction with an acid chloride or chloroformate of the formula R1COC1 at a temperature between 0 °C and ambient in organic solvent such as dichloromethane, chloro form or 1,2-dichloroethane in the presence of a tertiary amine base such as triethylamine or diisopropylethyl amine.
Alternatively, a compound of formula 1' may be obtained from a compound of formula 8 by reaction with a carboxylic acid of the formula R1COOH and a standard coupling agent such as 2-chloro-l,3-dimethyl-2-imidazolium hexafluorophosphate, or carbodiimide reagents such as dicyclohexylcarbodiimide or l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride at a temperature between 0 °C and ambient in organic solvent such as dichloromethane or tetrahydrofuran in the presence of a tertiary amine base such as triethylamine or diisopropylethylamine.
A compound of formula V may alternatively be obtained from a compound of formula 8 by reaction with a isocyanate or isothiocyanate of the formula RNCO or RNCS respectively at a temperature between 0 °C and ambient in organic solvent such as dichloromethane or tetrahydrofuran, optionally in the presence of a tertiary amine base such as triethylamine or diisopropylethylamine.
A compound of formula 1' may also be obtained from a compound of formula 8 by reaction with a sulfonyl chloride of the formula R1SO2Cl at a temperature between 0 °C and ambient in organic solvent such as dichloromethane or tetrahydrofuran, in the presence of a tertiary amine base such as triethylamine or diisopropylethylamine.
Alternatively, a compound of formula 1' may be obtained from a compound of formula 8 by reaction, with an aryl or heteroaryl compound of formula Ax-L where L is a leaving group such as halide (especially fluoride), such as a 2-halopyridine, a 2-halopyrimidine, a 4-halopyridine, a 2-halopyrazine or such like at a temperature between 50 °C and 150 °C in a solvent such as dimethylsulfoxide in the presence of a strong base such as sodium hydride.
Compounds of formula 8 may be obtained by reacting compounds of formula 9 with compounds of formula 5 (in scheme I) at a temperature of between ambient and 100 °C in organic solvent such as dichloromethane, chloroform or 1,2-dichloroethane in the presence of an acid such as trifluoroacetic acid for typically 4 to 12 hours, followed by addition of a
reducing agent such as tnethylsilane and reaction at a temperature of ambient to 100 °C until the reaction is complete.
Alternatively, Compounds of formula 8 may be obtained by reacting compounds of formula 9 with compounds of formula 5 at a temperature of between 0 °C and 100 °C in organic solvent such as dichloromethane, chloroform or 1,2-dichloroethane in the presence of an acid such as hydrochlonc acid, or trifluoroacetic acid and a co-solvent of either water or methanol or ethanol, or in the presence of a Lewis acidic metal salt such as zinc(II) dihalide. The intermediates formed (compounds of formula (9a)) are subsequently treated with a reducing agent such as sodium borohydride, sodium (triacetoxy)borohydride, sodium cyanoborohydride or such like at ambient temperature in organic solvent such as ethanol or chloroform.
Compounds of formula 8 may also be obtained by the hydrolysis of compounds of formula la (which are also a sub-set of compounds of formula 1) preferably with an aqueous acid, typically 6 N hydrochloric acid at reflux temperature.
Compounds of formula 9 may be obtained from compounds of formula 10 by reaction with methoxymethyl(triphenyl)phosphonium chloride or the corresponding bromide salt and a base such as potassium tert-butoxide at a temperature of 0 °C to ambient in tetrahydrofuran.
Compounds of formula 10 may be obtained by reacting compounds of formula 11 with an aqueous solution of acid, typically 6 N hydrochloric acid at reflux temperature. Compounds of formula 11 may be obtained from compounds of formula 12 by reaction with an electrophile of the formula R8-L, where L is chloride, bromide, iodide or a sulfonate (e.g. mesylate or tosylate) or similar leaving group at between ambient temperature and 100 °C, typically around 60 °C in an organic solvent such as dichloromethane, chloroform or 1,2-dichloroethane in the presence of an excess of a tertiary amine base such as triethylamine or diisopropylethylamine and optionally catalysed by halide salts such as sodium iodide, potassium iodide or tetrabutylammonium iodide.
Compounds of formula 12 are known compounds or may be obtained from known compounds by known techniques.
Certain compounds of formula 8, 9, 9a, 10 and 11 are novel and as such form a further aspect of the invention.
The skilled person will readily recognise that it is possible to interconvert one compound of formula I to other compounds of formula I and examples of such procedures are given in schemes III, IV, V, Va and VI below.
(Scheme Removed)
Compounds of formula I where R8 is optionally substituted cinnamyl may be prepared by the reactions in scheme VII below where R4, R5 , R 4 and Rs are as defined above. The scheme is illustrated in Examples 8 - 12.
SCHEME VII
(Scheme Removed)
pounds of formula (I) in which R and R together are an oxo group and R1, R4
and R8 are as defined above may be made by the methods of WO 0145707 as set out in scheme VIII below.
(Scheme Removed)
Compounds of formula (I) in which R2 and R3 together are an oxo group and and R8 are as defined above may be made from compounds of formula 4a by the methods of scheme X below.
(Scheme Removed)
The compounds of formula (I) can be used to combat and control infestations of insect pests such as Lepidoptera, Diptera, Hemiptera, Thysanoptera, Orthoptera, Dictyoptera, Coleoptera, Siphonaptera, Hymenoptera and Isoptera and also other invertebrate pests, for example, acarine, nematode and mollusc pests. Insects, acarines, nematodes and molluscs are hereinafter collectively referred to as pests. The pests which may be combated and controlled by the use of the invention compounds include those pests associated with agriculture (which term includes the growing of crops for food and fibre products), horticulture and animal husbandry, companion animals, forestry and the storage of products
of vegetable origin (such as fruit, grain and timber); those pests associated with the damage of man-made structures and the transmission of diseases of man and animals; and also nuisance pests (such as flies).
Examples of pest species which may be controlled by the compounds of formula (I) include: Myzuspersicae (aphid), Aphis gossypu (aphid), Aphis fabae (aphid), Lygus spp. (capsids), Dysdercus spp. (capsids), Nilaparvata lugens (planthopper), Nephotettixc incticeps (leafhopper), Nezara spp. (stinkbugs), Euschistus spp. (stinkbugs), Leptoconsa spp. (stinkbugs), Franklimella occidentalis (thrip), Thrips spp. (thrips), Leptmotarsa decemlineata (Colorado potato beetle), Anthonomus grandis (boll weevil), Aonidiella spp. (scale insects), Trialeurodes spp. (white flies), Bemisia tabaci (white fly), Ostrinia nubilalis (European com borer), Spodoptera littoralis (cotton leafworm), Heliothis virescens (tobacco budworm), Helicoverpa armigera (cotton bollworm), Helicoverpa zea (cotton bollworm), Sylepta derogata (cotton leaf roller), Pieris brassicae (white butterfly), Plutella xylostella (diamond back moth), Agrotis spp. (cutworms), Chilo suppressalis (rice stem borer), Locusta migratoria (locust), Chortiocetes terminifera (locust), Diabrotica spp. (rootworms), Panonychus ul/mi (European red mite), Panonychus citri (citrus red mite), Tetranychus urticae (two-spotted spider mite), Tetranychus cinnabarinus (carmine spider mite), Phyllocoptruta oleivora (citrus rust mite), Polyphagotarsonemus latus (broad mite), Brevipalpus spp. (flat mites), Boophilus microplus (cattle tick), Dermacentor variabilis (American dog tick), Ctenocephalides felis (cat flea), Liriomyza spp. (leafminer), Musca domestica (housefly), Aedes aegypti (mosquito), Anopheles spp. (mosquitoes), Culex spp. (mosquitoes), Lucillia spp. (blowflies), Blattella germanica (cockroach), Periplaneta americana (cockroach), Blatta orientalis (cockroach), termites of the Mastotermitidae (for example Mastotermes spp.), the Kalotermitidae (for example Neotennes spp.), the Rhinotermitidae (for example Coptotermes formosanus, Reticulitermes flavipes, R. speratu, R. virginicus, R. hesperus, and R. santonensis) and the Termitidae (for example Globitermes sulphureus), Solenopsis geminala (fire ant), Monomorium pharaonis (pharaoh's ant), Damalinia spp. and Linognathus spp. (biting and sucking lice), Meloidogyne spp. (root knot nematodes), Globodera spp. and Heterodera spp. (cyst nematodes), Pratylenchus spp. (lesion nematodes), Rhodopholus spp. (banana burrowing nematodes), Tylenchulus spp.(citrus nematodes), Haemonchus contortus (barber pole worm), Caenorhabditis elegans(vinegar
eelworm), Trichostrongylus spp. (gastro intestinal nematodes) and Deroceras reticulatum (slug).
The invention therefore provides a method of combating and controlling insects, acarines, nematodes or molluscs which comprises applying an insecticidally, acaricidally, nematicidally or molluscicidally effective amount of a compound of formula (I), or a composition containing a compound of formula (I), to a pest, a locus of pest, or to a plant susceptible to attack by a pest, The compounds of formula (I) are preferably used against insects, acarines or nematodes.
The term "plant" as used herein includes seedlings, bushes and trees. In order to apply a compound of formula (I) as an insecticide, acaricide, nematicide or molluscicide to a pest, a locus of pest, or to a plant susceptible to attack by a pest, a compound of formula (I) is usually formulated into a composition which includes, in addition to the compound of formula (I), a suitable inert diluent or carrier and, optionally, a surface active agent (SFA). SFAs are chemicals which are able to modify the properties of an interface (for example, liquid/solid, liquid/air or liquid/liquid interfaces) by lowering the interfacial tension and thereby leading to changes in other properties (for example dispersion, emulsification and wetting). It is preferred that all compositions (both solid and liquid formulations) comprise, by weight, 0.0001 to 95%, more preferably 1 to 85%, for example 5 to 60%, of a compound of formula (I). The composition is generally used for the control of pests such that a compound of formula (I) is applied at a rate of from 0.lg tol0kg per hectare, preferably from lg to 6kg per hectare, more preferably from lg to 1kg per hectare.
When used in a seed dressing, a compound of formula (I) is used at a rate of 0.000lg to lOg (for example 0.001 g or 0.05g), preferably 0.005g to l0g, more preferably 0.005g to 4g, per kilogram of seed.
In another aspect the present invention provides an insecticidal, acaricidal, nematicidal or molluscicidal composition comprising an insecticidally, acaricidally, nematicidally or molluscicidally effective amount of a compound of formula (I) and a suitable carrier or diluent therefor. The composition is preferably an insecticidal, acaricidal, nematicidal or molluscicidal composition.
In a still further aspect the invention provides a method of combating and controlling pests at a locus which comprises treating the pests or the locus of the pests with an insecticidally, acaricidally, nematicidally or molluscicidally effective amount of a
composition comprising a compound of formula (I). The compounds of formula (I) are preferably used against insects, acarines or nematodes.
The compositions can be chosen from a number of formulation types, including dustable powders (DP), soluble powders (SP), water soluble granules (SG), water dispersible granules (WG), wettable powders (WP), granules (GR) (slow or fast release), soluble concentrates (SL), oil miscible liquids (OL), ultra low volume liquids (UL), emulsifiable concentrates (EC), dispersible concentrates (DC), emulsions (both oil in water (EW) and water in oil (EC)), micro-emulsions (ME), suspension concentrates (SC), aerosols, fogging/smoke formulations, capsule suspensions (CS) and seed treatment formulations. The formulation type chosen in any instance will depend upon the particular purpose envisaged and the physical, chemical and biological properties of the compound of formula (I).
Dustable powders (DP) may be prepared by mixing a compound of formula (I) with one or more solid diluents (for example natural clays, kaolin, pyrophyllite, bentonite, alumina, montmorillonite, kieselguhr, chalk, diatomaceous earths, calcium phosphates, calcium and magnesium carbonates, sulphur, lime, flours, talc and other organic and inorganic solid carriers) and mechanically grinding the mixture to a fine powder.
Soluble powders (SP) may be prepared by mixing a compound of formula (I) with one or more water-soluble inorganic salts (such as sodium bicarbonate, sodium carbonate or magnesium sulphate) or one or more water-soluble organic solids (such as a polysaccharide) and, optionally, one or more wetting agents, one or more dispersing agents or a mixture of said agents to improve water dispersibility/solubility. The mixture is then ground to a fine powder. Similar compositions may also be granulated to form water soluble granules (SG). Wettable powders (WP) may be prepared by mixing a compound of formula (I) with one or more solid diluents or carriers, one or more wetting agents and, preferably, one or more dispersing agents and, optionally, one or more suspending agents to facilitate the dispersion in liquids. The mixture is then ground to a fine powder. Similar compositions may also be granulated to form water dispersible granules (WG).
Granules (GR) may be formed either by granulating a mixture of a compound of formula (I) and one or more powdered solid diluents or carriers, or from pre-formed blank granules by absorbing a compound of formula (I) (or a solution thereof, in a suitable agent) in a porous granular material (such as pumice, attapulgite clays, fuller's earth, kieselguhr, diatomaceous earths or ground corn cobs) or by adsorbing a compound of formula (I) (or a
solution thereof, in a suitable agent) on to a hard core material (such as sands, silicates, mineral carbonates, sulphates or phosphates) and drying if necessary. Agents which are commonly used to aid absorption or adsorption include solvents (such as aliphatic and aromatic petroleum solvents, alcohols, ethers, ketones and esters) and sticking agents (such as polyvinyl acetates, polyvinyl alcohols, dextrins, sugars and vegetable oils). One or more other additives may also be included in granules (for example an emulsifying agent, wetting agent or dispersing agent).
Dispersible Concentrates (DC) may be prepared by dissolving a compound of formula (I) in water or an organic solvent, such as a ketone, alcohol or glycol ether. These solutions may contain a surface active agent (for example to improve water dilution or prevent crystallisation in a spray tank).
Emulsifiable concentrates (EC) or oil-in-water emulsions (EW) may be prepared by dissolving a compound of formula (I) in an organic solvent (optionally containing one or more wetting agents, one or more emulsifying agents or a mixture of said agents). Suitable organic solvents for use in ECs include aromatic hydrocarbons (such as alkylbenzenes or alkylnaphthalenes, exemplified by SOLVESSO 100, SOLVESSO 150 and SOLVESSO 200; SOLVESSO is a Registered Trade Mark), ketones (such as cyclohexanone or methylcyclohexanone) and alcohols (such as benzyl alcohol, furfuryl alcohol or butanol), N-alkylpyrrolidones (such as N-methylpyrrolidone or N-octylpyrrolidone), dimethyl amides of fatty acids (such as C8-C10 fatty acid dimethylamide) and chlorinated hydrocarbons. An EC product may spontaneously emulsify on addition to water, to produce an emulsion with sufficient stability to allow spray application through appropriate equipment. Preparation of an EW involves obtaining a compound of formula (I) either as a liquid (if it is not a liquid at room temperature, it may be melted at a reasonable temperature, typically below 70oC) or in solution (by dissolving it in an appropriate solvent) and then emulsifiying the resultant liquid or solution into water containing one or more SFAs, under high shear, to produce an emulsion. Suitable solvents for use in EWs include vegetable oils, chlorinated hydrocarbons (such as chlorobenzenes), aromatic solvents (such as alkylbenzenes or alkylnaphthalenes) and other appropriate organic solvents which have a low solubility in water.
Microemulsions (ME) may be prepared by mixing water with a blend of one or more solvents with one or more SFAs, to produce spontaneously a thermodynamically stable isotropic liquid formulation. A compound of formula (I) is present initially in either the
water or the solvent/SFA blend. Suitable solvents for use in MEs include those hereinbefore described for use in in ECs or in EWs. An ME may be either an oil-in-water or a water-in-oil system (which system is present may be determined by conductivity measurements) and may be suitable for mixing water-soluble and oil-soluble pesticides in the same formulation. An ME is suitable for dilution into water, either remaining as a microemulsion or forming a conventional oil-in-water emulsion.
Suspension concentrates (SC) may comprise aqueous or non-aqueous suspensions of finely divided insoluble solid particles of a compound of formula (I). SCs may be prepared by ball or bead milling the solid compound of formula (I) in a suitable medium, optionally with one or more dispersing agents, to produce a fine particle suspension of the compound. One or more wetting agents may be included in the composition arid a suspending agent may be included to reduce the rate at which the particles settle. Alternatively, a compound of formula (I) may be dry milled and added to water, containing agents hereinbefore described, to produce the desired end product.
Aerosol formulations comprise a compound of formula (I) and a suitable propellant (for example n-butane). A compound of formula (I) may also be dissolved or dispersed in a suitable medium (for example water or a water miscible liquid, such as n-propanol) to provide compositions for use in non-pressurised, hand-actuated spray pumps.
A compound of formula (I) may be mixed in the dry state with a pyrotechnic mixture to form a composition suitable for generating, in an enclosed space, a smoke containing the compound.
Capsule suspensions (CS) may be prepared in a manner similar to the preparation of EW formulations but with an additional polymerisation stage such that an aqueous dispersion of oil droplets is obtained, in which each oil droplet is encapsulated by a polymeric shell and contains a compound of formula (I) and, optionally, a carrier or diluent therefor. The polymeric shell may be produced by either an interfacial polycondensation reaction or by a coacervation procedure. The compositions may provide for controlled release of the compound of formula (I) and they may be used for seed treatment. A compound of formula (I) may also be formulated in a biodegradable polymeric matrix to provide a slow, controlled release of the compound.
A composition may include one or more additives to improve the biological performance of the composition (for example by improving wetting, retention or distribution
on surfaces; resistance to rain on treated surfaces; or uptake or mobility of a compound of formula (I)). Such additives include surface active agents, spray additives based on oils, for example certain mineral oils or natural plant oils (such as soy bean and rape seed oil), and blends of these with other bio-enhancing adjuvants (ingredients which may aid or modify the action of a compound of formula (I)).
A compound of formula (I) may also be formulated for use as a seed treatment, for example as a powder composition, including a powder for dry seed treatment (DS), a water soluble powder (SS) or a water dispersible powder for slurry treatment (WS), or as a liquid composition, including a flowable concentrate (FS), a solution (LS) or a capsule suspension (CS). The preparations of DS, SS, WS, FS and LS compositions are very similar to those of respectively, DP, SP, WP, SC and DC compositions described above. Compositions for treating seed may include an agent for assisting the adhesion of the composition to the seed (for example a mineral oil or a film-forming barrier).
Wetting agents, dispersing agents and emulsifying agents may be surface SFAs of the cationic, anionic, amphoteric or non-ionic type.
Suitable SFAs of the cationic type include quaternary ammonium compounds (for example cetyltrimethyl ammonium bromide), imidazolines and amine salts.
Suitable anionic SFAs include alkali metals salts of fatty acids, salts of aliphatic monoesters of sulphuric acid (for example sodium lauryl sulphate), salts of sulphonated aromatic compounds (for example sodium dodecylbenzenesulphonate, calcium dodecylbenzenesulphonate, butylnaphthalene sulphonate and mixtures of sodium di-isopropyl- and tri-isopropyl-naphfhalene sulphonates), ether sulphates, alcohol ether sulphates (for example sodium laureth-3-sulphate), ether carboxylates (for example sodium laureth-3-carboxylate), phosphate esters (products from the reaction between one or more fatty alcohols and phosphoric acid (predominately mono-esters) or phosphorus pentoxide (predominately di-esters), for example the reaction between lauryl alcohol and tetraphosphoric acid; additionally these products may be ethoxylated), sulphosuccinamates, paraffin or olefine sulphonates, taurates and lignosulphonates.
Suitable SFAs of the amphoteric type include betaines, propionates and glycinates.
Suitable SFAs of the non-ionic type include condensation products of alkylene oxides such as ethylene oxide, propylene oxide, butylene oxide or mixtures thereof, with fatty alcohols (such as oleyl alcohol or cetyl alcohol) or with alkylphenols (such as octylphenol,
nonylphenol or octylcresol); partial esters derived from long chain fatty acids or hexitol anhydrides; condensation products of said partial esters with ethylene oxide; block polymers (comprising ethylene oxide and propylene oxide); alkanolamides; simple esters (for example fatty acid polyethylene glycol esters); amine oxides (for example lauryl dimethyl amine oxide); and lecithins.
Suitable suspending agents include hydrophilic colloids (such as polysaccharides, polyvinylpyrrolidone or sodium carboxymethylcellulose) and swelling clays (such as bentonite or attapulgite).
A compound of formula (I) may be applied by any of the known means of applying pesticidal compounds. For example, it may be applied, formulated or unformulated, to the pests or to a locus of the pests (such as a habitat of the pests, or a growing plant liable to infestation by the pests) or to any part of the plant, including the foliage, stems, branches or roots, to the seed before it is planted or to other media in which plants are growing or are to be planted (such as soil surrounding the roots, the soil generally, paddy water or hydroponic culture systems), directly or it may be sprayed on, dusted on, applied by dipping, applied as a cream or paste formulation, applied as a vapour or applied through distribution or incorporation of a composition (such as a granular composition or a composition packed in a water-soluble bag) in soil or an aqueous environment.
A compound of formula (I) may also be injected into plants or sprayed onto vegetation using electrodynamic spraying techniques or other low volume methods, or applied by land or aerial irrigation systems.
Compositions for use as aqueous preparations (aqueous solutions or dispersions) are generally supplied in the form of a concentrate containing a high proportion of the active ingredient, the concentrate being added to water before use. These concentrates, which may include DCs, SCs, ECs, EWs, MEs SGs, SPs, WPs, WGs and CSs, are often required to withstand storage for prolonged periods and, after such storage, to be capable of addition to water to form aqueous preparations which remain homogeneous for a sufficient time to enable them to be applied by conventional spray equipment. Such aqueous preparations may contain varying amounts of a compound of formula (I) (for example 0.0001 to 10%, by weight) depending upon the purpose for which they are to be used.
A compound of formula (I) may be used in mixtures with fertilisers (for example nitrogen-, potassium- or phosphorus-containing fertilisers). Suitable formulation types
include granules of fertiliser. The mixtures suitably contain up to 25% by weight of the compound of formula (I).
The invention therefore also provides a fertiliser composition comprising a fertiliser and a compound of formula (I).
The compositions of this invention may contain other compounds having biological activity, for example micronutrients or compounds having fungicidal activity or which possess plant growth regulating, herbicidal, insecticidal, nematicidal or acaricidal activity.
The compound of formula (I) may be the sole active ingredient of the composition or it may be admixed with one or more additional active ingredients such as a pesticide, fungicide, synergist, herbicide or plant growth regulator where appropriate. An additional active ingredient may: provide a composition having a broader spectrum of activity or increased persistence at a locus; synergise the activity or complement the activity (for example by increasing the speed of effect or overcoming repellency) of the compound of formula (I); or help to overcome or prevent the development of resistance to individual components. The particular additional active ingredient will depend upon the intended utility of the composition. Examples of suitable pesticides include the following:
a) Pyrethroids, such as permethrin, cypermethrin, fenvalerate, esfenvalerate, deltamethrin, cyhalothrin (in particular Iambda-cyhalothrin), bifenthrin, fenpropathrin, cyfluthrin, tefluthrin, fish safe pyrethroids (for example ethofenprox), natural pyrethrin, tetramethrin, s-bioallethrin, fenfluthrin, prallethrin or 5-benzyl-3-furylmethyl-(E)-(lR,3S)-2,2-dimethyl-3-(2-oxothiolan-3-ylidenemethyl)cyclopropane carboxylate;
b) Organophosphates, such as, profenofos, sulprofos, acephate, methyl parathion, azinphos-methyl, demeton-s-methyl, heptenophos, thiometon, fenamiphos, monocrotophos, profenofos, tnazophos, methamidophos, dimethoate, phosphamidon, malathion, chlorpyrifos, phosalone, terbufos, fensulfothion, fonofos, phorate, phoxim, pirimiphos-methyl, pirimiphos-ethyl, fenitrothion, fosthiazate or diazinon;
c) Carbamates (including aryl carbamates), such as pirimicarb, triazamate, cloethocarb, carbofuran, furathiocarb, ethiofencarb, aldicarb, thiofurox, carbosulfan, bendiocarb, fenobucarb, propoxur, methomyl or oxamyl;
d) Benzoyl ureas, such as diflubenzuron, triflumuron, hexaflumuron, flufenoxuron or chlorfluazuron;
e) Organic tin compounds, such as cyhexatin, fenbutatin oxide or azocyclotin;
f) Pyrazoles, such as tebufenpyrad and fenpyroximate;
g) Macrolides, such as avermectins or milbemycins, for example abamectin, emamectin benzoate, ivermectin, milbemycin, spinosad or azadirachtin;
h) Hormones or pheromones;
i) Organochlorine compounds such as endosulfan, benzene hexachloride, DDT, chlordane or
dieldrin;
j) Amidines, such as chlordimeform or amitraz;
k) Fumigant agents, such as chloropicrin, dichloropropane, methyl bromide or metam;
1) Chloronicotinyl compounds such as imidacloprid, thiacloprid, acetamiprid, nitenpyram or
thiamethoxam;
m) Diacylhydrazines, such as tebufenozide, chromafenozide or methoxyfenozide;
n) Diphenyl ethers, such as diofenolan or pyriproxifen;
o) Indoxacarb;
p) Chlorfenapyr; or
q) Pymetrozine.
In addition to the major chemical classes of pesticide listed above, other pesticides having particular targets may be employed in the composition, if appropriate for the intended utility of the composition. For instance, selective insecticides for particular crops, for example stemborer specific insecticides (such as cartap) or hopper specific insecticides (such as buprofezin) for use in rice may be employed. Alternatively insecticides or acaricides specific for particular insect species/stages may also be included in the compositions (for example acaricidal ovo-larvicides, such as clofentezine, flubenzimine, hexythiazox or tetradifon; acaricidal motilicides, such as dicofol or propargite; acaricides, such as bromopropylate or chlorobenzilate; or growth regulators, such as hydramethylnon, cyromazine, methoprene, chlorfluazuron or diflubenzuron).
Examples of fungicidal compounds which may be included in the composition of the invention are (E)-N-methyl-2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxy-iminoacetamide (SSF-129), 4-bromo-2-cyano-N,N-dimethy]-6-trifluoromethylbenzimidazole-1 -sulphonamide, α-[N-(3-chloro-2,6-xylyl)-2-methoxyacetamido]--butyrolactone, 4-chloro-2-cyano-N,N-dimethyl-5-p-tolylimidazole-l -sulfonamide. (IKF-916, cyamidazosulfamid), 3-5-dichloro-N-(3-chloro-1 -ethyl-l-methyl-2-oxopropyl)-4-methylbenzamide (RH-7281, zoxamide), N-ally]-4,5,-dimethyl-2-trimethylsilylthiophene-3-carboxamide (MON65500), N-
(l-c)'ano-l,2-dimethylpropyl)-2-(2,4-dichlorophenoxy)propionamide (AC382042), N-(2-methoxy-5-pyridyl)-cyclopropane carboxamide, acibenzolar (CGA245704), alanycarb, aldimorph, anilazine, azaconazole, azoxystrobin, benalaxyl, benomyl, biloxazol, bitertanol, blasticidin S, bromuconazole, bupirimate, captafol, captan, carbendazim, carbendazim chlorhydrate, carboxin, carpropamid, carvone, CGA41396, CGA41397, chinomethionate, chlorothalonil, chlorozolinate, clozylacon, copper containing compounds such as copper oxychloride, copper oxyquinolate, copper sulphate, copper tallate and Bordeaux mixture, cymoxanil, cyproconazole, cyprodinil, debacarb, di-2-pyridyl disulphide 1,1'-dioxide, dichlofluanid, diclomezine, dicloran, diethofencarb, difenoconazole, difenzoquat, diflumetorim, O,O-di-iso-propyl-S-benzyl thiophosphate, dimefiuazole, dimetconazole, dimethomorph, dimethirimol, diniconazole, dinocap, dithianon, dodecyl dimethyl ammonium chloride, dodemorph, dodine, doguadine, edifenphos, epoxiconazole, ethirimol, ethyl(Z)-N-benzyl-N([methyl(methyl-thioethylideneaminooxycarbonyl)amino]thio)-ß -alaninate, etridiazole, famoxadone, fenamidone (RPA407213), fenarimol, fenbuconazole, fenfuram, fenhexamid (KBR2738), fenpiclonil, fenpropidin, fenpropimorph, fentin acetate, fentin hydroxide, ferbam, ferimzone, fluazinam, fludioxonil, flumetover, fluoroimide, fluquinconazole, flusilazole, flutolanil, flutriafol, folpet, fuberidazole, furalaxyl, furametpyr, guazatine, hexaconazole, hydroxyisoxazole, hymexazole, imazalil, imibenconazole, iminoctadine, iminoctadine triacetate, ipconazole, iprobenfos, iprodione, iprovalicarb (SZX0722), isopropanyl butyl carbamate, isoprothiolane, kasugamycin, kresoxim-methyl, LYl86054, LY211795, LY248908, mancozeb, maneb, mefenoxam, mepanipyrim, mepronil, metalaxyl, metconazole, metiram, metiram-zinc, metominostrobin, myclobutanil, neoasozin, nickel dimethyldithiocarbamate, nitrothal-iso propyl, nuarimol, ofurace, organomercury compounds, oxadixyl, oxasulfuron, oxolinic acid, oxpoconazole, oxycarboxin, pefurazoate, penconazole, pencycuron, phenazin oxide, phosetyl-Al, phosphorus acids, phthalide, picoxystrobin (ZA1963), polyoxin D, polyram, probenazole, prochloraz, procymidone, propamocarb, propiconazole, propineb, propionic acid, pyrazophos, pyrifenox, pyrimethanil, pyroquilon, pyroxyfur, pyrrolnitrin, quaternary ammonium compounds, quinomethionate, quinoxyfen, quintozene, sipconazole (F-155), sodium pentachlorophenate, spiroxamine, streptomycin, sulphur, tebuconazole, tecloftalam, tecnazene, tetraconazole, thiabendazole, thifluzamid, 2-(thiocyanomethylthio)benzothiazole, thiophanate-methyl, thiram, timibenconazole, tolciofos-methyl, tolylfluanid, triadimefon, triadimenol, triazbutil,
triazoxide, tncyclazole, tridemorph, trifloxystrobin (CGA279202), triforine, triflumizole, triticonazole, validamycin A, vapam, vinclozolin, zineb and ziram.
The compounds of formula (I) may be mixed with soil, peat or other rooting media for the protection of plants against seed-borne, soil-bome or foliar fungal diseases.
Examples of suitable synergists for use in the compositions include piperonyl butoxide, sesamex, safroxan and dodecyl imidazole.
Suitable herbicides and plant-growth regulators for inclusion in the compositions will depend upon the intended target and the effect required.
An example of a rice selective herbicide which may be included is propanil. An example of a plant growth regulator for use in cotton is PIX™.
Some mixtures may comprise active ingredients which have significantly different physical, chemical or biological properties such that they do not easily lend themselves to the same conventional formulation type. In these circumstances other formulation types may be prepared. For example, where one active ingredient is a water insoluble solid and the other a water insoluble liquid, it may nevertheless be possible to disperse each active ingredient in the same continuous aqueous phase by dispersing the solid active ingredient as a suspension (using a preparation analogous to that of an SC) but dispersing the liquid active ingredient as an emulsion (using a preparation analogous to that of an EW). The resultant composition is a suspoemulsion (SE) formulation.
The invention is illustrated by the following Examples:
EXAMPLE 1
This Example illustrates the preparation of compound V-22, l-Acetyl-5-chloro-l'-[trans-3-(4-chlorophenyl)allyl]spiro[indoline-3,4'-piperidine]

l-(2-Chloropyridin-4-yl)carbonylspiro[indoline-3,4'-piperidine] trifluoroacetic acid salt was prepared according to the procedures described in Example 2.
l-(2-Chloropyridin-4-yl)carbonylspiro[indoline-3,4'-piperidine] trifluoroacetic acid salt (0.25 g) was suspended in dioxane (2 ml) and paraformaldehyde (0.08 g) was added. The mixture was stirred and heated to 90°C for 20 minutes. 2-(4-fluorophenyl)vinylboronic acid (0.10 g) was dissolved in dioxane (2 ml) and the resulting solution was added to the salt/paraformaldehyde mixture and the resulting mixture was heated to 90°C for 24 hours. The mixture was allowed to cool and evaporated to dryness in vacuo. The residue was partitioned between dichloromethane and water, and the organic layer was washed with aqueous sodium carbonate solutioh (1M) and evaporated. The crude product was purified by column chormatography (SiO2, first column in dichloromethane:triethylamine 95:5, then a second column starting with neat dichloromethane, then a gradient from ethyl acetate:hexane: triethylamine 25:75:1 to 95:0:5) to give 0.20 g (76%) of the desired product. MS (ES+) 462/464 M+H+.
Compounds 1-23, XXIX-1,1-21,1-2, XXVI-2 (followed by treatment with hydrogen peroxide in methanol) and XXVI-22 (followed by treatment with hydrogen peroxide in methanol), were prepared according to procedures analogous to those described in Example 6.
EXAMPLE 7
This Example illustrates the preparation of compound I-212, 5-Cyano-l-(2-chloropyridin-4-y])carbonyl-1'-[trans-3-(4-chlorophenyl)allyl]spiro[indoline-3,4'-piperidine]
(Formula Removed)
5-Iodo-l-(2-chloropyridin-4-yl)carbonyl-1'-[trans-3-(4-chlorophenyl)allyl]spiro[indoline-
3,4'-piperidine] was prepared by procedures analogous to those described in Example 2.
5-Iodo-l-(2-chloropyridin-4-yl)carbonyl-1'-[trans-3-(4-chlorophenyl)allyl]spiro[indoline-
3,4'-piperidine] (0.05 g) was dissolved in anhydrous THF (5 ml) under an atmosphere of dry
nitrogen. Potassium cyanide (0.011 g) and copper (I) iodide (0.016 g) were added and the
mixture was degassed for 15 minutes. Tetrakis(triphenylphosphine) palladium (0.005 g) was
added and the mixture was heated to reflux for 28 hours. The reaction mixture was diluted
with dichloromethane (50 ml) and washed with water (30 ml). The aqueous layer was
extracted with dichloromethane (2 x 40 ml) and the combined organic layers were dried
(magnesium sulfate), filtered and evaporated in vacuo to give a colourless oil that was
purified by prep. TLC (SiO2, EtOAc:Hexane:Et3N 1:1:0.01) to give 0.041 g (95%) of the
desired product. MS (ES+) 503/505/507 M+H+.
Compounds XXIX-201,1-282,1-232 were prepared according to standard procedures
analogous to those described in Example 7. Compound XXV-222 was prepared by treating
compound XXIX-201 with potassium carbonate in methanol. Compound 1-222 was prepared
by re-acylation of compound XXV-222 under standard conditions.
EXAMPLE 8
This example illustrates the preparation of compound XXX-51
l-(2-chloropyridin-4-yl)carbonyl-5-chloro-r-[(E)-3-(4-trifluoromethyl-phenyl)
allyl]spiro[indolin-3,4'-piperidine]
(Formula Removed)
Step 1: Preparation of (E)-3-(4-trifluorornethyl-phenyl)-acrylic acid ethyl ester Ethyl diethylphosphonoacetate (84 g) in 1,2-dimethoxyethane (100 ml) was added dropwise to a suspension of sodium hydride (55% in oil, 15g) in 1,2-dimethoxyethane (500 ml) at room temperature. 4-Trifluorobenzaldehyde (43.5 g) dissolved in 1,2-dimethoxyethane (100 ml) was then added and the resulting mixture was stirred at room temperature for 4 h. The reaction was quenched by addition of water (400 ml), diluted with diethyl ether (700 ml), the organic phase was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was recrystallised from hexane to give 37 g of the desired product (61%) which was characterized by its mass and NMR spectra. Step 2: Preparation of (E)-3-(4-trifluoromethyl-phenyl)-prop-2-en-l-oI To a solution of the ester obtained in step 1 (37.1 g) in toluene (310 ml) at 0°C was added dropwise diisobutylaluminium hydride (1.2M in toluene, 317 ml) and the solution was stirred at 0°C for 1 h. Water (47.6 ml) was carefully added at 0°C followed by sodium hydroxide 2M (47.6 ml) and finally water (95.1 ml). The mixture was allowed to stir at room temperature for 1 h. After filtration, the solution was washed with hydrochloric acid 2N, water and brine, dried over sodium sulfate and concentrated in vacuo to give 29.5 g of the desired alcohol as a solid (96%) which was characterized by its mass and NMR spectra. Step 3: Preparation of l-((E)-3-bromo-propenyl)-4-trifluoromethyl-benzene To a solution of the alcohol obtained in step 2 (10 g) in dimethylacetamide (100 ml) at room temperature were added triphenylphosphine (23 g) and carbon tetrabromide (29 g). The resulting solution was stirred at room temperature for 1 h, poured into water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate and filtered over silica gel to give 13 g of the desired product as a white solid (95 %) which was characterized by its mass and NMR spectra.
Step 4: Preparation of l-(2-chloropyridin-4-yl)carbonyl-5-chloro-1'-[(E)-3-(4-trifluoromethyl-phenyl) allyl]spirol"indolin-3,4,-piperidine]
To a stirred suspension of-(2-chloropyridin-4-yl)carbonyL5-chloro-spiro[indolin-3,4'-piperidine] (20 g) and diisopropylethylamine (18.2 ml) in acetonitrile (200 ml) was added the allylic bromide obtained in step 3(11.6 g) and the reaction mixture was stirred overnight at room temperature. The solution was diluted with ethyl acetate (200 ml), washed with brine (3x100 ml), dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (SiO2, ethyl acetate:hexane:triethylamine 95:5:0.1 to ethyl acetate:methanol:triethylamine 95:5:0.1) to give 18.9 g of the desired product (82%). Mp = 130°C.
Compounds XXX-82, XXX-83, XXX-84, XXX-85, XXX-86, XXX-87, XXX-91 and XXX-92 were prepared according to standard procedures analogous to those described in Example 8.
EXAMPLE 9
This example illustrates the preparation of compound XXX-113 l-(2-chloropyridin-4-yl)carbonyl-5-chloro-l'-[(Z)-3-(4-chlorophenyl)-2-fluoro-allyl]spiro[indolin-3,4'-piperidine]
(Formula Removed)
Step 1: Preparation of (Z)-3-(4-chloro-phenyl)-2-fluoro-acrylic acid methyl ester By analogy with: Cousseau, J. et al. Tetrahedron Lett. 1993, 43, 6903 4-Chlorobenzaldehyde (0.66 g) was added to a suspension of diethylfluorooxalacetate, sodium salt (1 g, prepared from diethyl oxalate, efhylfluoroacetate and sodium hydride according to Alberg et al. J. Am. Chem. Soc. 1992, 3542) in tetrahydrofuran (20 ml) at 0°C, and the resulting'mixture was stirred 1 h at 0°C then 3 h at 80°C. The reaction mixture was concentrated in vacuo, diluted with diethyl ether, washed with aqueous sodium bicarbonate,
vvater and bnne, dried over sodium sulfate and concentrated in vacuo to afford a crude
residue (1.2 g) which was used diretly in the next step.
Step 2: Preparation of (2)-3-(4-chloro-phenyl)-2-fluoro-prop-2-en-l-ol
Step 3: Preparation of l-((Z)-3-bromo-2-fluoro-propenyl)-4-chloro-benzene
Step 4: Preparation of 1 -(2-chloropyridin-4-yl)carbonyl-5-chloro-l '-[(Z)-3-(4-ch]orophenyl)-2-fluoro-allyl]spiro[indolin-3,4'-piperidine]
Step 2 to 4 were carried out following the procedure described in Example 8, step 2-4 to give 0.17 g of the desired product (41%) which was characterized by its mass and NMR spectra. MS (ES+) 530.
Compound XXX-114 was prepared according to standard procedures analogous to those described in Example 9.
EXAMPLE 10 This example illustrates the preparation of 1-25
l-(2-chloropyridin-4-yl)carbonyl-5-chloro-1'-[trans-3-(4-methoxyphenyl) allyl]spiro[indolin-3,4'-piperidine]
(Formula Removed)
Step 1: Preparation of l-(4-Methoxy-phenyl)-prop-2-en-l-ol
To a solution of p-anisaldehyde (1.54 ml) in tetrahydrofuran (20 ml) at -10°C under argon was added dropwise vinyl magnesium bromide (1M in THF, 12.5 ml). The solution was stirred overnight at room temperature and quenched by addition of saturated aqueous ammonium chloride (20 ml). The organic phase was separated, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (SiO2, ethyl acetatexyclohexan 7:3) to give 1.05 g of the desired product as a colorless oil (51 %) which was characterized by its mass and NMR spectra.
Step 2: Preparation of l-((E)-3-Chloro-propenyl)-4-methoxy-benzene
To a solution of the allylic alcohol obtained in step 1 (200 mg) in diethyl ether (3 ml) was
added thionyl chloride (0.087 ml) and the solution was stirred at room temperature for 1 h.
The solution was concentrated in vacuo to give 221 mg of the desired product (100%) as a
colorless solid. Mp= 70°C.
Step 3: Preparation of l-(2-chioropyridin-4-yl)carbonyl-5-chloro-1'-[trans-3-('4-methoxy-
phenyl)allyl]spiro[indolin-3.4'-piperidine]
Alkylation of l-(2-chloropyridin-4-yl)carbonyl-5-chloro-spiro[indolin-3,4'-piperidine] (0.43
g) with l-((E)-3-chloro-propenyl)-4-methoxy
-benzene obtained in step 2 (0.22 g) was carried out following the procedure described in
example 101, step 4 to afford 0.36 g of the title compound (59%) which was characterized by
its mass and NMR spectra. MS (ES+) 509. Mp = 83-85°C.
EXAMPLE 11
This example illustrates the preparation of XXX-115
l-(2-chloropyridin-4-yl)carbonyl-5-chloro-l'-[(Z)-3-(4-chlorophenyl)-3-chloro-allyl]spiro[indolin-3,4'-piperidine]
(Formula Removed)
Step 1: Preparation of (Z)-3-chloro-3-(4-chloro-phenyl)-acrylic acid methyl ester By analogy with : Tanaka, M. et al. J. Am. Chem. Soc. 1998, 120, 12365 To a solution of 4-chlorophenylacetylene (100 mg) and Rh(CO)(PPh3)2Cl (5 mg) in toluene (3 ml) was added methyl chloroformate (0.17 ml) and the mixture was stirred in a sealed tube at 110°C for 10 h. The reaction mixture was concentrated in vacuo and subjected to column chromatography (SiO2, ethyl acetate:cyclohexan 1:9) to give 104 mg of the desired product as a brown solid (61%) which was characterized by its mass and NMR spectra. Mp= 40°C.
Step 2: Preparation of (Z)-3-chloro-3-(4-chloro-phenvl)-prop-2-en-l-ol
Following the procedure described in Example 8, step 2, (Z)-3-chloro-3-(4-chloro-phenyl)-
acrylic acid methyl ester (462 mg) was converted into the desired'product (391 mg, 96%)
which was characterized by its mass and NMR spectra.
Step 3: Preparation of l-chloro-4-((Z)-dichloro-propenyl)-benzene
To a solution of (Z)-3-chloro-3-(4-chloro-phenyl)-prop-2-en-l-ol (101 mg) in toluene (3 ml)
was added thionyl chloride (0.11 ml) and one drop of dimethylformamide. After 1 h, the
solution was concentrated in vacuo to afford 120 mg of the desired allylic chloride (100%) as
a colorless oil.
Step 4: Preparation of l-(2-chloropyridin-4-yl)carbonyl-5-chloro-l'-[(Z)-3-(4-
chlorophenyl)-3-chloro-allyl]spiro[indolin-3,4'-piperidine]
Alkylation of l-(2-chloropyridin-4-yl)carbonyl-5-chloro-spiro[indolin-3,4'-piperidine] (0.18 g) with l-chloro-4-((Z)-l,3-dichloro-propenyl)-benzene obtained in step 3 (0.11 g) was carried out following the procedure described in example 101, step 4 to afford 0.17 g of the title compound (64%) as a foam which was characterized by its mass and NMR spectra. MS (ES+) 548.
EXAMPLE 12
This example illustrates the preparation of XXX-90
l-(2-chloropyridin-4-yl)carbonyl-5-chloro-l'-[(Z)-3-(4-chlorophenyl)-3-fluoro-allyl]spiro[indolia-3,4'-piperidine]
(Formula Removed)
Step 1: Preparation of (Z)-3-(4-Chloro-phenyl)-3-fluoro-acrylic acid methyl ester By analogy with: Cousseau, J. J. Chem. Soc. Chem. Commun. 1989, 1493
To a solution of (4-chloro-phenyl)-propynoic acid methyl ester (5.36 g) in dirnethylformamide (60 ml) was added cesium fluoride (11.4 g) and potassium hydrogen fluoride (2.73 g) in water (5.4 ml) and the mixture was stirred at 80°C for 8 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 ml), the organic phase washed with water (3x50 ml) and brine (3x20 ml), dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (SiO2, ethyl acetatexyclohexan 1:9) to give 1.06 g of the desired product (20%) which was characterized by its mass and NMR spectra.
Step 2: Preparation of (Z)-3-(4-chloro-phenyl)-3-fluoro-prop-2-en-l-ol
Step 3: Preparation of l-Chloro-4-((Z)-3-chloro-l-fluoro-propenyl)-benzene
Step 4: Preparation of l-(2-chloropyridin-4-yl)carbonyl-5-chloro-l '-[(Z)-3-(4-chlorophenyl)-3-fluoro-allyl]spiro[indolin-3,4'-piperidine]
Step 2 to 4 were carried out following the procedure described in Example 11, step 2-4 to give 163 mg of the desired product (42%) which was characterized by its mass and NMR spectra. MS (ES+) 531.
Compounds XXX-88 and XXX-90 were prepared according to standard procedures analogous to those described in Example 12.
EXAMPLE 13
This example illustrates the preparation of compound XXX-121 and XXX-94, 1-carboxylic acid (4-chloro-phenyl)-amide-5-fluoro-1'-[trans-3-(4-chlorophenyl)allyl]spiro[indoline-3,4,-piperidine].
(Formula Removed)
5-Fluoro-l '-[trans,-3-(4-chlorophenyl)allyl]spiro[indoline-3,4'-piperidine] was prepared according to a procedure analogous to that described in steps 1 to 4 of Example 4. Step 1: Preparation of Compound XXX-121, l-nitroso-5-fluoro-1'-[trans-3-(4-chlorophenyl)allyl]spirorindoline-3,4'-piperidine]
A solution of 5-fluoro-l,-[trans-3-(4-chlorophenyl)allyl]spiro[indoline-3,4'-piperidine] (5 g) in dichloromethane (15 ml) was added to a suspension of wet silica gel (50% w/w in water, 2.9 g) and zinc chloride (5.73 g) in dichloromethane (15 ml) and the resulting mixture was stirred for 3.5 hours at room temperature. The reaction mixture was diluted with ethyl acetate and the insoluble residues were removed by filtration. The filtrate was washed with saturated aqueous sodium bicarbonate solution, water and brine, dried over sodium sulfate and the solvents were evaporated in vacuo to afford 5.13 g (95%) of the desired nitroso-amine as a solid. MS (ES+) 386.
(Formula Removed)
Step 2: Preparation of l-amino-5-fluoro-1'-trans-3-(4-chlorophenyl)allyl]spiro[indoline-
3,4'-piperidine1
A solution of l-nitroso-5-fluoro-1'-[trans-3-(4-chlorophenyl)allyl]spiro[indoline-3,4,-
piperidine] (5 g) in tetrahydrofuran (60 ml) was added dropwise to a suspension of lithium
aluminium hydride (1.47 g) in tetrahydrofuran (60 ml) at 0°C and the resulting mixture was
stirred at room temperature for 2.5 hours. Water (4.8 ml) was carefully added, followed by 15
% aqueous sodium hydroxide (4.8 ml), and finally water (14.4 ml). The mixture was stirred
for 0.5 hours, diluted with ethyl acetate, dried over sodium sulfate, and filtered. The solvents
were evaporated in vacuo to afford 5.1 g (100%) of the desired amino-indoline as a solid. MS
(ES+) 372.
Step 3: Preparation of 1-carboxylic acid (4-chloro-phenyl)-amide-5-fluoro-1'-[trans-3-(4-
chlorophenyl)allyl]spiro[indoline-3,4'-piperidinel.
2-Chloroisonicotinoyl chloride (1.2 g) was added to a stirred solution of l-amino-5-fluoro-
1'-[trans-3-(4-chlorophenyl)allyl]spiro[indoline-3,4'-piperidine] (0.2 g) and triethylamine
(0.3 ml) in dichloromethane (4 ml) at room temperature. The mixture was stirred for 2 hours.
The reaction mixture was washed with water and the aqueous layer was extracted with
dichloromethane. The combined organic layers were dried (sodium sulfate), filtered and
evaporated. The crude product was purified by chromatography [SiO2, ethyl acetate-methanol
(96:4)'to give 0.13 g (48%) of the desired product. MS (ES+) 511.
Compounds XXX-95, XXX-97, XXX-98 and XXX-99 were prepared according to standard
procedures analogous to those described in Example 13
EXAMPLE 14
This example illustrates the preparation of compound XXX-119, l-(4-chloro-phenyl)-urea-
5-fluoro-1'-[trans-3-(4-chlorophenyl)allyl]spiro[indoline-3,4'-piperidine].
(Formula Removed)
To a solution of 1 -amino-5-fluoro-l '-[trans-3-(4-chlorophenyl)allyl]spiro[indoline-3,4'-
piperidine] (0.2 g) in tetrahydrofuran (2 ml) was added 4-chlorophenyl isocyanate (70 mg)
and the mixture was stirred at room temperature for 10 mm. The solvent was evaporated in
vacuo and the residue purified by preparative HPLC to afford the title compound (49%) as a
solid. MS (ES+) 525.
Compounds XXX-100, XXX-101, XXX-102 and XXX-103 were prepared according to
standard procedures analogous to those described in Example 14.
EXAMPLE 15 This example illustrates the preparation of compound XXX-102 N'-[5-chloro-l'-[trans-3-
(4-chlorophenyl)allyl]spiro[indoline-3,4'-piperidine]-l-yl]-N,N-dimethylacetamidine
(Formula Removed)
To a solution of l-amino-5-chloro-1'-[trans-3-(4-chlorophenyl)allyl]spiro[indoline-3,4'-
piperidine] (0.15 g) in tetrahydrofuran (2 ml) was added N,N-dimethylacetam'ide dimethyl
acetal (0.2 g) and the mixture was stirred at 70°C for 24 hours. The solvent was evaporated
in vacuo and the residue purified by chromatography [SiO2; ethyl acetate-mefhanol (9:1) to
give 35 mg (20%) of the desired product. MS (ES+) 457.
EXAMPLE 16
This example illustrates the preparation of compound XXX-105 l-[carboxylic acid (2-
methoxy-ethyl)-amide]-5-chloro-1'-[trans-3-(4-chlorophenyl)allyl]spiro[indoline-3,4,-piperidine].
(Formula Removed)
5-Chloro-1'-[trans-3-(4-chlorophenyl)allyl]spiro[indoline-3,4'-piperidine] (2.5 g) was added to a suspension of sodium bicarbonate (1.7 g) in acetonitrile (45 ml) and the resulting mixture cooled to 0°C. 4-Nitrophenyl chloroformate (2.54 g) was then added dropwise and the resulting solution stirred at 0°C for 2 hours. 3 ml of the solution was added to a solution of 2-methoxy-ethylamine (315 mg) and triethylamine (0.3 ml) in dimethylformamide (10 ml) and the resulting mixture was stirred at 50°C for 3 hours. The solution was cooled to room temperature, poured into water, extracted three times with ethyl acetate. The organic phase was dried over sodium sulfate, filtered, and the solvents were removed in vacuo. The residue was purified by reverse-phase HPLC to afford the desired product (57% yield). MS (ES+) 458.
Compounds XXX-104, XXX-106, XXX-107, XXX-108, XXX-109, XXX-110, XXX-111 and XXX-112 were prepared according to standard procedures analogous to those described in Example 16.
EXAMPLE 17
Preparation of compound XXVI-1 - l,2-Dihydro-l-(4-nitrobenzoyl)-l '-(3-phenyl-2-propeny])-spiro[3H-indole-3-4'-piperidine]
(Formula Removed)
In the experimental details to follow, standard wash will refer to the following washing sequence: dimethylformamide, dichloromethane, dimethylformamide, dichloromethane, methanol, dichloromethane, methanol (X2), tert-butyl methyl ether (X2) and resin swelling protocol will be based on a standard of 10 ml of solvent per gram of resin. Compound identities and purities were determined using High Performance Liquid Chromatography coupled Mass Spectrometry (HPLC-MS) and Proton Nuclear Magnetic Resonance (1H NMR) on selected compounds. REM resin was prepared from commercially available (hydroxymethyl)polystyrene resin and acryloyl chloride. The loading of the resins were assumed to be constant at 1.2 mmolg-1 throughout the synthesis.
Step A: Loading of 4-Formylpiperidine dimethyl acetal onto REM resin (Resin A) REM resin (10 g, 12 mmol) was swollen in dimethylformamide (100 ml). A solution of 4-formylpiperidine dimethyl acetal (2.86 g, 18 mmol) in dimethylformamide (10 ml) was then added. The reaction was left to shake at room temperature for 18 hours. The resulting resin
was then filtered, washed according to the standard procedure and dried in vacuo to afford 11.83 g (96% yield) of the desired resm A .
Step B: Preparation of Solid supported 4-Formylpiperidine (Resin B)
A 100 ml solution of trifluoroacetic acid / dichloromethane / water (49 : 49 : 2) was added to
resin A (10 g, 12 mmol) and the mixture was then shaken at room temperature for 2 hours.
The resulting resin was then filtered, washed using dichloromethane (x3), methanol,
dichloromethane, methanol, tert-butyl methyl ether (x2) and dried in vacuo to afford 9.48 g
of the desired resin B, which was stored at -50°C under nitrogen.
Step C: Preparation of Solid supported Spiro[3H-indole-3,4'-piperidine] (Resin C)
To resin B (1 g, 1.2 mmol) was added a solution of 5% trifluoroacetic acid in
dichloromethane (10 ml) followed by addition of anisole (0.0026 g, 0.024 mmol). The
mixture was degassed with nitrogen for 10 minutes, and phenylhydrazine (0.39 g, 3.6 mmol)
was added. The reaction mixture was stirred under nitrogen and heated to reflux for 36 hours.
The mixture was then filtered, washed according to the standard wash cycle and dried in
vacuo to afford 1.09 g of the desired resin C, which was used immediately in Step D.
Step D: Preparation of Solid supported l,2-Dihydro-spiro[3H-indole-3,4'-piperidine] (Resin
D)
To resin C (1 g, 1.2 mmol), swollen in anhydrous dichloromethane (10 ml) was added
sodium tnacetoxyborohydride (0.51 g, 2.4 mmol) as a solid. The reaction mixture was stirred
at room temperature under nitrogen for 2 hours. The resin was then filtered, washed
according to the standard wash cycle and dried in vacuo to afford 0.95 g of the desired resin
D, which was stored at -50°C under nitrogen.
Step E: Preparation of Solid supported l,2-Dihydro-l-(4-nitrobenzoyl)-spiro[3H-indole-3,4'-
piperidine] (Resin E)
Resin D (0.5 g, 0.6 mrnol) was swollen in anhydrous dichloromethane (5 ml). To the mixture
was added 4-nitrobenzoyl chloride (0.33 g, 1.8 mmol) and N,N-diisopropylethylamine (0.42
ml, 2.4 mmol). After shaking at room temperature for 18 hours, the resin was filtered,
washed according to the standard wash cycle and dried in vacuo to afford 0.53 g of the
desired resin E.
Step F: Quatemization of Solid supported l,2-Dihydro-l-(4-nitrobenzoyl)-spiro[3H-indole-
3,4'-piperidine] (Resin F)
To resin E (0.1 g. 0.12 mmol) in anhydrous dimethylformamide (1 ml) was added cinnamyl
bromide (0.12 g, 0.6 mmol). The reaction mixture was shaken at room temperature for 48
hours. The resulting resin was then washed according to the standard wash cycle to afford
0.11 g of the desired resin F, which was used immediately in Step G.
Step G: Preparation of l,2-Dihydro-l-(4-nitrobenzoyl)-l '-(3-phenyl-2-propenyl)-spiro[3H-
indole-3,4'-piperidine]
To resin F (0.11 g, 0.132 mmol) in anhydrous dimethylformamide (1.1 ml) was added
Amberlite IRA-93 (previously washed with 10% N,N-
diisopropylethylamine/dimethylformarnide) (0.11 g). The mixture was shaken at room
temperature for 36 hours. The dimethylformamide filtrate was then collected and
concentrated under reduced pressure. The resin was further washed with dichloromethane
and methanol. All filtrates were then combined and concentrated in vacuo to afford 0.052 g
(88% yield) of the desired compound as a pale yellow oil.
By an analogous procedure other compounds were prepared including compound XVI-21,
5-Chloro-l,2-dihydro-l-(4-nitrobenzoyl)-1'-(3-phenyl-2-propenyl)-spiro[3H-indole-3-4'-
piperidine]
EXAMPLE 18
This example illustrates the preparation of compound XXX-72, l-(2-chloropyridin-4-yl)carbonyl-5-chloro-1'-[(Z)-3-(4-methylthiophenyl) allyl]spiro[indolin-3,4'-piperidine]